Risk factors for 3-month mortality in bedridden patients with hospital-acquired pneumonia: A multicentre prospective study.

BACKGROUND: Mortality among patients with hospital-acquired pneumonia (HAP) is quite high; however, information on risk factors for short-term mortality in this population remains limited. The aim of the current study was to identify the risk factors for mortality in bedridden patients with HAP during a 3-month observation period.
METHODS: A secondary data analysis was conducted. In total, 1141 HAP cases from 25 hospitals were included in the analysis. Univariate and multilevel regression analyses were performed to identify the risk factors for mortality.
RESULTS: During the 3-month observation period, there were 189 deaths among bedridden patients with HAP. The mortality rate in this study was 16.56%. Multilevel regression analysis showed that ventilator-associated pneumonia (OR = 2.034, 95%CI: 1.256, 3.296, p = 0.004), pressure injuries (OR = 2.202, 95%CI: 1.258, 3.852, p = 0.006), number of comorbidities (OR = 1.076, 95%CI: 1.016,1.140, p = 0.013) and adjusted Charlson Comorbidity Index score (OR = 1.210, 95%CI: 1.090, 1.343, p<0.001) were associated with an increased risk of mortality, while undergoing surgery with general anaesthesia (OR = 0.582, 95%CI: 0.368, 0.920, p = 0.021) was associated with a decreased risk of mortality.
CONCLUSIONS: The identification of risk factors associated with mortality is an important step towards individualizing care plans. Our findings may help healthcare workers select high-risk patients for specific interventions. Further study is needed to explore whether appropriate interventions against modifiable risk factors, such as reduced immobility complications or ventilator-associated pneumonia, could improve the prognoses.

Introduction

Hospital-acquired pneumonia (HAP), or nosocomial pneumonia, is a pulmonary infection that develops in patients hospitalized for more than 48 hours in the intensive care unit (ICU) or in other wards [1].

Ventilator-associated pneumonia (VAP) is a subcategory of HAP that occurs in mechanically ventilated patients more than 48 hours after tracheal intubation [2]. HAP is one of the most common hospital-acquired infections [3]. In the United States, HAP is the second most common nosocomial infection, with an incidence ranging from 5 to more than 20 cases per 1000 hospital admissions [4]. In China, the incidence of hospital-acquired infections in all hospitalized patients was 3.22–5.22%, among which hospital-acquired lower respiratory tract infections accounted for 1.76–1.94% [5]. HAP/VAP account for the largest proportion of hospital-acquired infections worldwide.

HAP can have negative consequences for patients, including prolonged hospital stay, decreased quality of life and high mortality [6,7]. Despite improvements in prevention, antimicrobial therapy, and supportive care [1], HAP remains an important cause of morbidity and mortality [8]. The mortality rate for HAP ranges from 38% to more than 70% [9]. In Japan, the 30-day mortality was 23.8% [10]. A recent review found that the incidence of VAP ranges from two to 16 episodes per 1000 ventilator-days, with an attributable mortality rate of 3–17% [11].

Compared to a large number of studies on the risk factors for mortality among community acquired pneumonia (CAP) patients [12,13], only a relatively small number of studies have focused on HAP. Feng et al found that the risk factors included age >70 years, ICU admission, blood lymphocyte count, multidrug-resistant gram-negative bacteria (MDR-GNB) infection, and blood urea nitrogen (BUN) level [14]. Another study in a psychiatric hospital found that the mortality rate in HAP patients tended to increase with increasing severity classification [15]. Another recent study found that comorbidities positively contribute to the risk of death from pneumonia in the hospital; however, the study did not distinguish their types or origins [16]. The specific factors associated with HAP remain unknown.

Materials and methods

The aim, design and setting of the study

The current study aimed to: (i) describe the mortality rate of bedridden patients with HAP and (ii) explore the risk factors for mortality among the study population.

The data for this study were obtained from a database of multicentre baseline survey data from a national research programme that aimed to explore and construct a standardized nursing care model for immobility complications (including pressure injuries, pneumonia, deep vein thrombosis, and urinary tract infection) among bedridden inpatients [17]. The details of the programme have been described elsewhere [17-19]. In brief, the study was carried out in 25 hospitals (six tertiary, 12 non-tertiary and seven community hospitals) in northern China (Beijing), central China (Henan and Hubei), southern China (Guangdong), eastern China (Zhejiang), and western China (Sichuan) from November 2015 to June 2016. Participants were recruited from wards with high proportions of bedridden patients, including neurology, neurosurgery, general medicine, orthopaedics, geriatrics and critical care units.

Study population

Patients were eligible for the study if they were: (a) adult patients (≥18 years old); (b) bedridden for at least one day after admission in the selected ward (bedridden was defined as the patients’ basic physiological needs being carried out in bed except for active or passive bedside standing/wheelchair use for examination or treatment) [20]; and (c) diagnosed with HAP. Patients were excluded if they had more than one type of major complication of immobility (pressure injuries, deep vein thrombosis, urinary tract infection) at the time of enrollment. Overall, 1141 patients were included in the analysis.

Measures

HAP

HAP was defined as pneumonia occurring at least 48 hours after hospital admission, excluding any infection present at the time of admission [5]. It was diagnosed based on a combination of clinical, laboratory and radiological data by physicians and was recorded in the patient’s medical record. The criteria for the diagnosis of HAP included new pulmonary infiltrate confirmed by X-ray or computed tomography (occurring ≥48 hours after admission) associated with at least one of the following: new or worsening cough with or without sputum production, fever (temperature >37.8 °C) or hypothermia (<35.6 °C), leucocytosis, left shift, or leucopenia based on local normal values [5].

Sociodemographic and disease characteristics

Patients’ sociodemographic characteristics (such as age, gender and health insurance) were self-reported by the patients. Mobility at admission, pressure injuries, comorbidities and other medical data information were obtained from audits of the patients’ hospital charts and electronic health records. The age-adjusted Charlson Comorbidity Index (ACCI) was calculated based on the diagnosis at discharge [21]. International Classification of Diseases, 10th Edition (ICD-10) codes were used for the diagnosis code and calculation.

Outcomes

In this study, 3-month all-cause mortality was evaluated as the primary outcome. Mortality information was observed and recorded for 90 days after the enrollment date regardless of whether the patient died before or after discharge.

Data collection

Eligible participants were identified and enrolled by pre-trained nurses in the selected wards. In total, 787 registered nurses from 25 general hospitals were appointed to perform patient recruitment and data collection. They screened and recorded the participating patients’ information daily. An electronic data collection (EDC) system was designed for data collection for this study. The evaluation of patients and demographic data were collected on the day of recruitment. Diagnosis of HAP and other related variables were collected on a daily basis during the hospitalization period. After discharge, participants received a telephone follow-up call every two weeks until their 90th day after enrollment. A strictly standardized procedure were applied to ensure the quality of data collection. A coordinator in each hospital was responsible for internal logistics and checking compliance to the study protocol. The head nurses of the selected wards regularly audited the data recorded by the data collectors. Moreover, an independent quality control team regularly supervised the data collection through on-site quality control and case verification measures and provided feedback via emails, phones, and meetings.

Ethical considerations

The study was approved by the Ethics Committee of Peking Union Medical College Hospital (S-700). Patients received verbal and written informed consent. If patients had a cognitive impairment (such as sedation), their family members was asked to provide the consent. All data were anonymous or were kept confidential.

Data analysis

Continuous and categorical variables are presented as the means (standard deviations (SDs)) and n (%), respectively. The variables were organized into three levels: hospital, ward, and patient. Intra-class coefficients (ICCs) were calculated to gauge the potential effect of clustering on the results. We used the Mann-Whitney U test, χ2 test, or Fisher’s exact test to compare differences between survivors and non-survivors where appropriate. To explore the risk factors associated with mortality, univariate and multivariate analyses were conducted using a multilevel mixed-effects model with two random intercept models to evaluate the effect of the hospital and ward. The model considered that patients from the same hospital or ward may have unmeasured characteristics that affect outcomes associated with those hospital or wards differently than those associated with different hospitals or wards. Death status was coded as the number 0 or 1, with 0 indicating survival and 1 indicating death. Covariates that were considered to be important factors based on prior literature and the univariate analysis were considered candidates for inclusion in the models. Hospital-level variables included hospital type (tertiary and non-tertiary hospitals), and patient-level variables included age, gender, education level, health insurance, smoking status, body mass index (BMI), mobility at admission, surgery with general anaesthesia, VAP, length confined to bed, pressure injuries and comorbidities. The statistical analyses were carried out using SAS 9.4 for Windows (SAS Institute, Cary, North Carolina, USA). All tests were 2-tailed, with p<0.05 considered significant.

Results

Among 1141 hospitalized bedridden patients with HAP, 189 deaths occurred during the 3-month follow-up period, leading to an overall mortality rate of 16.56%.

Demographic characteristics and the main clinical features of the patient groups are compared in Table 1. Compared to survivors, non-survivors tended to be older, have a lower BMI, and did not undergo surgery with general anaesthesia; additionally, they were more likely to be admitted to a non-tertiary hospital and have dependent mobility at admission. They also had more comorbidities and a higher age-adjusted Charlson Comorbidity Index score than survivors.

Table 1

Baseline characteristics of bedridden patients with hospital-acquired pneumonia (n = 1,141).

Variables	Total	Non-survivor (n = 189)	Survivor (n = 952)	t/χ2/Z	p value
Gender
Male	695(60.91)	122(64.55)	573(60.19)	1.260	0.2617
Female	446(39.09)	67(35.45)	379(39.81)
Age, years	62.80±16.58	70.38±15.02	61.30±16.47	7.032	<0.0001
Age group
18~64	575(50.39)	54(28.57)	521(54.73)	58.023	<0.0001
65~74	247(21.65)	42(22.22)	205(21.53)
≥75	319(27.96)	93(49.21)	226(23.74)
Highest education level
Primary school or below	520(45.57)	97(51.32)	423(44.43)	3.770	0.1518
Junior or senior high school	488(42.77)	69(36.51)	419(44.01)
College degree or above	133(11.66)	23(12.17)	110(11.55)
Health insurance
No	277(19.89)	32(16.93)	195(20.48)	1.248	0.2639
Yes	914(80.11)	157(83.07)	757(79.52)
Smoking status
No	847(74.23)	148(78.31)	699(73.42)	1.965	0.1609
Yes	294(25.77)	41(21.69)	253(26.58)
Body Mass Index (BMI)
<18.5	97(8.51)	29(15.34)	68(7.15)	15.489	0.0004
18.5~23.9	592(51.93)	99(52.38)	493(51.84)
>23.9	451(39.56)	61(32.28)	390(41.01)
Mobility at admission
Independent	277(24.28)	27(14.29)	250(26.26)	12.301	<0.001
Dependent	864(75.72)	162(85.71)	702(73.74)
Surgery with general anaesthesia
No	733(64.24)	150(79.37)	583(61.24)	22.553	<0.001
Yes	408(35.76)	39(20.63)	369(38.76)
VAP
No	957(83.87)	150(79.37)	807(84.77)	3.405	0.0650
Yes	184(16.13)	39(20.63)	145(15.23)
Length of confinement to bed
1~7	232(20.33)	31(16.40)	201(21.11)	3.829	0.1474
8~14	317(27.78)	62(32.80)	255(26.79)
≥15	592(51.88)	96(50.79)	496(52.10)
Hospital type
Non tertiary	205(17.97)	54(28.57)	151(15.86)	17.284	<0.001
Tertiary	936(82.03)	135(71.43)	801(84.14)
Pressure injuries
No	1041(91.24)	160(84.66)	881(92.54)	12.264	<0.001
Yes	100(8.76)	29(15.34)	71(7.46)
Comorbidities (n = 1,135)
Number of comorbidities (IQR)	5(5)	7(6)	5(5)	5.8922	< .0001
1–4	480(43.52)	48(26.37)	432(46.91)	26.064	<0.001
≥5	623(56.48)	134(73.63)	489(53.09)
ACCI score, median (IQR)	3(4)	5(3)	3(3)	8.391	<0.001
Mild (ACCI 0–2)	489(43.08)	38(20.11)	451(47.67)	75.398	<0.001
Moderate (ACCI 3–4)	314(27.67)	49(25.93)	265(28.01)
Severe (ACCI≥5)	332(29.25)	102(53.97)	230(24.31)

Note: IQR: Interquartile range; VAP: Ventilator-associated pneumonia; ACCI: Age-adjusted Charlson Comorbidity Index.

Table 2 shows the results of the univariate and multivariate multilevel mixed-effects model analysis after adjustment for a series of covariates. In the multilevel model, we found that VAP (OR = 2.034, 95%CI: 1.256, 3.296, p = 0.004), pressure injuries (OR = 2.202, 95%CI: 1.258, 3.852, p = 0.006), number of comorbidities (OR = 1.076, 95%CI: 1.016,1.140, p = 0.013) and adjusted Charlson Comorbidity Index score (OR = 1.210, 95%CI: 1.090, 1.343, p<0.001) were associated with an increased risk of mortality, while undergoing surgery with general anaesthesia (OR = 0.582, 95%CI: 0.368, 0.920, p = 0.021) was associated with a decreased risk of mortality.

Table 2

Risk factors associated with death among bedridden patients with hospital-acquired pneumonia (n = 1,141).

Variables	Univariate OR (95% CI)	p value	Multivariable OR (95% CI)	P value
Female (vs male)	0.823(0.592, 1.144)	0.247	0.729(0.494, 1.076)	0.111
Age, years	1.039(1.027, 1.051)	<0.001	1.005(0.989, 1.021)	0.580
College degree or above (vs primary school or below)	0.983(0.565, 1.710)	0.950	0.965(0.516, 1.807)	0.998
Junior or senior high school (vs primary school or below)	0.760(0.522, 1.106)	0.144	0.828(0.543, 1.264)	0.365
Health insurance (vs no insurance)	1.219(0.794, 1.871)	0.366	1.076(0.676, 1.712)	0.757
Current smoker (vs nonsmoker)	1.258(0.530, 1.129)	0.183	0.705(0.448, 1.109)	0.131
BMI<18.5 (vs BMI 18.5~23.9)	2.148(1.287, 3.583)	0.005	1.519(0.862, 2.679)	0.143
BMI >23.9 (vs BMI 18.5~23.9)	0.771(0.535, 1.110)	0.155	0.807(0.543, 1.198)	0.278
Dependent mobility at admission (vs independent mobility)	2.265(1.446, 3.440)	<0.001	1.467(0.882, 2.440)	0.140
Surgery with general anaesthesia (vs no surgery)	0.383(0.259, 0.569)	<0.001	0.582(0.368, 0.920)	0.021
VAP (vs none VAP)	1.483(0.990, 2.223)	0.056	2.034(1.256, 3.296)	0.004
Length of confinement to bed	1.102(0.896, 1.357)	0.357	0.905(0.713, 1.148)	0.410
Admission to a tertiary hospital (vs nontertiary hospital)	0.469(0.315, 0.687)	<0.001	0.625(0.358, 1.090)	0.093
Pressure injuries (vs no pressure injury)	2.565(1.565, 4.201)	<0.001	2.202(1.258, 3.852)	0.006
Number of comorbidities	1.168(1.112, 1.228)	<0.001	1.076(1.016, 1.140)	0.013
ACCI score	1.327(1.238, 1.423)	<0.001	1.210(1.090, 1.343)	<0.001

Note: CI, confidence interval; VAP: Ventilator-associated pneumonia; AACI, age-adjusted Charlson Comorbidity Index.

Discussion

This multicentre prospective study identified a relatively high mortality rate as well as several risk factors for mortality in bedridden inpatients with HAP. In particular, VAP, pressure injuries, number of comorbidities, and adjusted Charlson Comorbidity Index score were associated with increased risk of death, while undergoing surgery with general anaesthesia was associated with a decreased risk of mortality.

Despite advances in new guidelines and significant efforts to improve the care and outcomes associated with HAP, we found that the overall 3-month mortality among hospitalized bedridden patients with HAP remains high (16.56%), which is in concordance with other previous studies [22,23]. A study conducted in the United States found that mortality in adults hospitalized with pneumonia was 13.0%, 23.4%, and 30.6% at 30 days, 6 months, and 1 year, respectively [23]. The results highlight the importance of taking specific measures to improve the prognosis of bedridden patients with HAP.

In the multivariate multilevel analysis, we found several risk factors for mortality among bedridden patients with HAP, among which pressure injuries had the highest odds ratio. A meta-analysis found that patients complicated with pressure injuries are estimated to have a two times higher risk of mortality compared to patients without pressure injuries [24]. Immobility complications, including pressure injuries, have been shown to be predictors of adverse outcomes and prognosis among bedridden patients [17]. Another study found that the mortality of patients with pressure injuries was as high as 66% in a 12-week median follow-up period [25]. Our study further indicated that pressure injuries are a good predictor of death. As this factor is modifiable, particular attention should be given to the prevention and treatment of pressure injuries and other immobility complications among the population.

Mortality was significantly higher in patients with VAP. Similar to our study, VAP was the leading cause of death in mechanically ventilated patients [26]. A recent study in the Chinese population found that the 30-day mortality rate of VAP patients was 42.8% [27]. A systematic review indicated that the attributable mortality of ventilator-associated pneumonia is mainly caused by increased length of ICU stay [28]. Together with the findings of the current study, this suggests that healthcare providers should pay more attention to patients with VAP to reduce their mortality.

The number of comorbidities was significantly associated with short-term mortality in our study. A previous study found that comorbidities positively contributed to the risk of death from pneumonia in the hospital, regardless of their type or origin [16]. Another study found an inconsistent result indicating that the number of comorbidities was not associated with mortality [29]. Reasons for the difference may be that, in that study, the study population was elderly (mean age: 81.6 years), and the majority had multiple comorbidities; few patients were aged <65 years or had few comorbidities. The participants in the current study were much younger (mean age: 62.80 years). An even distribution of the number of diseases simplifies the process of detecting the impact.

With regard to the severity of illness, previous studies have mainly focused on Pneumonia Severity Index (PSI) and CURB-65 score, which were mainly used to predict mortality in patients with CAP [30] and were seldom trained or designed in patients with HAP [31]. The lack of severity assessment tools specifically for this group of patients has limited the ability to early detection of poor prognosis among HAP patients. The current study added new evidence by exploring the role of chronic comorbidities in predicting HAP patients’ outcomes. We found that the ACCI score was an independent risk factor for mortality among HAP patients. The ACCI is widely used to predict mortality and has been validated in various clinical populations [21,32]. The results support the prognostic value of the ACCI score and indicate that the ACCI score may be useful for risk stratification and decision making of individual HAP patients. Future studies are necessary to compare its performance with CURB-65 and PSI and determine if this tool may be universally applied to HAP patients.

In addition to the above results, it noteworthy that patients who underwent surgery with general anaesthesia had a lower risk for mortality than those who did not. In the current study, 35.76% of patients underwent surgery with general anaesthesia. The reason might be that one of the most important surgical indications is a relatively good health condition.

Strengths and limitations

The current study provides detailed mortality information of bedridden patients with HAP over a 3-month period. The major strengths of this study were the multicentre design and large population of consecutively included and prospectively followed patients, which increased the generalizability of the results. However, there are still several limitations. First, this was a secondary data analysis; thus, there is a lack of other relevant clinical data, which might have increased the possibility of information bias and misclassification. Second, adjustments were made for demographic, clinical and microbiological variables. However, some important patient characteristics (pneumonia severity, co-infections, and types of bacteria) could not be analysed because they were not available in the database. Prospective studies with more specific evaluations are required to confirm the findings. Third, the present study used 3-month follow-up data, and the long-term risk factors for mortality therefore could not be determined. Future studies should extend the follow-up period and include large-scale related factors.

Conclusions

In the current study, we identified several factors (VAP, pressure injuries, numbers of comorbidities, ACCI and surgery with general anaesthesia) for mortality among bedridden HAP patients. These findings have great clinical significance for improving the prognosis of patients. Early identification and intervention for these patients, who are at high risk of mortality, will help to improve clinical outcomes. We recommend further research on whether the modification of factors associated with increased mortality, such as improving care quality to prevent immobility complications, could improve outcomes in bedridden HAP patients.

11 Dec 2020

PONE-D-20-25311

Risk factors for 3 - month mortality in bedridden patients with hospital - acquired pneumonia: a multicenter prospective study.

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Reviewer #1: The authors identified the risk factors for mortality in bedridden patients with HAP during a 3-month observation period. They found that intensive care unit (ICU) admission, number of comorbidities and adjusted Charlson Comorbidity Index score were associated with an increased risk of mortality. However, several previous studies have shown similar results that disease severity and presence of comorbidities are associated with poor prognosis. The authors should clarify new evidences of this study.

Reviewer #2: In the manuscript “3-month mortality in bedridden patients with hospital-acquired pneumonia; a multicenter prospective study”, Jiao et al report the results from a secondary analysis of a prospective observational study that included 1141 patients diagnosed with HAP from 25 hospitals. They describe associations between patient characteristics, ward status, and treatments factors (surgical and anesthesia) versus inpatient mortality. They report ICU admission and patient comorbidities to be positively associated with death, and surgery with GA and tertiary hospital admission to be negatively associated with death, and conclude that the findings could help providers identify patients with high.

The etiology and consequences of HAP are poorly characterized, and a large prospective study of patients with a standard sampling method has much potential for adding knowledge. However, as currently written, the analysis seems to fall short of advancing our understanding dramatically, and the conclusion that using the risk factors for decision-making does not seem to be supported by the results. Some makor concerns:

Sampling method: While the case definition of a bedridden patient and HAP was well described, the process of enrollment into the prospective cohort was not immediately clear. Were patients identified and enrolled by treating clinicians? Was there a screening process applied to all hospitalized patients? If the latter, how was this process applied? The authors mention that patients with major complications of immobility at the time of enrollment were excluded; what were these exlclusion criteria? What was the enrollment % of patients initially screened?

Treatments during the hospitalization including ventilator use, antibiotic use, and glucocorticoid use were listed as patient charcteristics. I do not typically view these factors as patient characteristics, as they are interventions that might be associated with the other patient characteristics and the outcomes in very complex ways. If the study is intended to be a cohort study and these interventions are being examined as potential independent risk factors for HAP, then the timing is also incredibly important and I was unable to discern at what point in the hospitalization – before or after the development of HAP – these interventioned were identified. The results would have very different meaning to me depending on this.

Conclusions: It is hard to glean what meaning the authors feel this study has to our understanding from the conclusion. It is not surpirising that comorbidities are associated with higher mortality; however, whether the aCCI score has utility over clinical judgment is not supported in this study. It is als not surpiring that patients in the ICU have higher mortlity risk, but the authors’ causal explanations when attempting to explain some associations (ie, ICU admission leading to ventilator use leading to mortality, or surgical admission � differences in quality of medical care � lower mortality) seem very far-reaching. It all is further muddied by an unclear picture of how these patients were identified, and how that identification process accounted for – or did not – the potential sampling bias that renders the findings difficult to generalize.

**********

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Reviewer #1: Yes: Mutsuo Yamaya

Reviewer #2: No

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Submitted filename: Review of PONE-D-20-25311.docx

Click here for additional data file.

22 Dec 2020

Dear Shane Patman,

Thank you for your letter and for the reviewers’ comments concerning our manuscript entitled “Risk factors for 3-month mortality in bedridden patients with hospital-acquired pneumonia: a multicentre prospective study” (ID: PONE-D-20-25311). Those comments were valuable and helpful for revising and improving the manuscript. We have taken the comments into careful consideration and have made corrections that we hope will be met with approval. Revised portions are marked in red in the paper. The main correction and the response to the reviewers’ comments are set out as below. We look forward to hearing from you regarding our submission. We would be glad to respond to any further questions and comments that you may have.

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Author response: Thank you for your important comments. We have carefully cited the references and revised the text thoroughly in the current study.

Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Partly

________________________________________

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

________________________________________

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Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors identified the risk factors for mortality in bedridden patients with HAP during a 3-month observation period. They found that intensive care unit (ICU) admission, number of comorbidities and adjusted Charlson Comorbidity Index score were associated with an increased risk of mortality. However, several previous studies have shown similar results that disease severity and presence of comorbidities are associated with poor prognosis. The authors should clarify new evidences of this study.

Author response: Thank you for your constructive and insightful advice about the findings. We agree that more evidence is needed to further clarify the study. We have included more patient-specific risk factors (including mobility at admission, immobility complications) and re-analysed the data. In the updated results, we additionally found that pressure injuries and VAP were risk factors for mortality among the population. The findings have great clinical implication for improving the prognosis of patients as they are modifiable factors. The detailed explanation and analysis of the results are described in the Discussion and Conclusion sections.

Reviewer #2: In the manuscript “3-month mortality in bedridden patients with hospital-acquired pneumonia; a multicenter prospective study”, Jiao et al report the results from a secondary analysis of a prospective observational study that included 1141 patients diagnosed with HAP from 25 hospitals. They describe associations between patient characteristics, ward status, and treatments factors (surgical and anesthesia) versus inpatient mortality. They report ICU admission and patient comorbidities to be positively associated with death, and surgery with GA and tertiary hospital admission to be negatively associated with death, and conclude that the findings could help providers identify patients with high.

The etiology and consequences of HAP are poorly characterized, and a large prospective study of patients with a standard sampling method has much potential for adding knowledge. However, as currently written, the analysis seems to fall short of advancing our understanding dramatically, and the conclusion that using the risk factors for decision-making does not seem to be supported by the results. Some makor concerns:

Sampling method: While the case definition of a bedridden patient and HAP was well described, the process of enrollment into the prospective cohort was not immediately clear. Were patients identified and enrolled by treating clinicians? Was there a screening process applied to all hospitalized patients? If the latter, how was this process applied? The authors mention that patients with major complications of immobility at the time of enrollment were excluded; what were these exlclusion criteria? What was the enrollment % of patients initially screened?

Author response: Thank you very much for your constructive advice about the sampling method. We apologize that this part was not described clearly in the original manuscript. We have revised the contents of this part of the manuscript (Page 3, line 140-151). The specific response to the questions you mentioned are listed as follows.

(1) The patients were identified and enrolled by pre-trained nurses. The screening process was only applied to bedridden patients (Page 3, line 140-144).

(2) The exclusion criteria were patients with more than one type of major complication of immobility (pressures injuries, deep vein thrombosis, and urinary tract infection) at the time of enrollment (Page 3, line 115-117).

(3) Regarding the enrollment percentage, we agree that it is an important indicator to the representativeness of the sample and have attempted to acquire the percentage. However, we failed because this was a secondary data analysis. We have mentioned this in the limitation section (Page 12, line 265-271).

Treatments during the hospitalization including ventilator use, antibiotic use, and glucocorticoid use were listed as patient charcteristics. I do not typically view these factors as patient characteristics, as they are interventions that might be associated with the other patient characteristics and the outcomes in very complex ways. If the study is intended to be a cohort study and these interventions are being examined as potential independent risk factors for HAP, then the timing is also incredibly important and I was unable to discern at what point in the hospitalization – before or after the development of HAP – these interventioned were identified. The results would have very different meaning to me depending on this.

Author response: Thank you very much for your careful review and constructive suggestions with regard to the risk factors. I am also grateful for the specific modification strategy. We agree that the treatment during hospitalization should not be viewed as patient characteristics, as they were affected by patients’ characteristics and may have impacted the outcomes in complicated ways. I have made comprehensive and detailed changes according to your suggestion. On one hand, in the risk factor candidates, we excluded the factors related to treatment, including ICU admission, ventilator use, antibiotic use, and glucocorticoid use. On the other hand, we further took more patient-specific factors into consideration, including mobility at admission and immobility complications (pressure injuries). We reanalysed the data and updated the results and discussions.

Conclusions: It is hard to glean what meaning the authors feel this study has to our understanding from the conclusion. It is not surpirising that comorbidities are associated with higher mortality; however, whether the aCCI score has utility over clinical judgment is not supported in this study. It is als not surpiring that patients in the ICU have higher mortlity risk, but the authors’ causal explanations when attempting to explain some associations (ie, ICU admission leading to ventilator use leading to mortality, or surgical admission � differences in quality of medical care � lower mortality) seem very far-reaching. It all is further muddied by an unclear picture of how these patients were identified, and how that identification process accounted for – or did not – the potential sampling bias that renders the findings difficult to generalize.

Author response: Thank you for your thoughtful comments. We agree that it is essential to make more specific and reasonable analyses and explanations on the relationship between the risk factors identified and mortality.

(1) In regard to comorbidities, previous studies on the comorbidities and mortality among pneumonia patients have mainly focused on PSI and CURB-65, both of which primarily use acute clinical findings to predict mortality. However, the role of chronic comorbidities in predicting outcomes is unclear. Therefore, we explored the ability of the ACCI to predict mortality in patients with HAP. We admit that more studies are needed on the performance and feasibility of ACCI. We have revised the discussion (Page 11, line 239-247).

(2) Regarding ICU admission, we excluded the variable in the multivariate analysis. As the reviewer suggested, it could not be a very good indicator to explain the mortality of HAP patients. In addition, ICU admission is also impacted by the patients’ decision making and total number of hospital ICU beds. In the updated results, we found that VAP increased the risk of mortality compared to non VAP patients. We have revised the discussion (Page 11, line 225-230).

________________________________________

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Mutsuo Yamaya

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: Response_letter_1223.docx

Click here for additional data file.

9 Mar 2021

PONE-D-20-25311R1

Risk factors for 3 - month mortality in bedridden patients with hospital - acquired pneumonia: a multicenter prospective study.

PLOS ONE

Dear Dr. Li,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Apr 23 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Shane Patman, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

For this revision it was fortuitous to continue with the same peer reviewers from the initial submission. The sentiment from this review cycle is predominantly positive. Reviewer 2 notes an opportunity for slight adjustment to the manuscript discussion to enhance clarity and provide direction for future research efforts, as detailed below.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: Excellent revision. All of my major questions were addressed. One minor comment - authors discuss previous severity assessment tools (PSI/CURB-65), but these were intended for use to predict 30-day mortality in patients with community-onset pneumonia - it should probably be highlighted that these tools were never trained or designed for the use in patients with HAP. The lack of severity assessment tools specifically for this group of patients could rather be highlighted.

**********

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Reviewer #1: No

Reviewer #2: Yes: Barbara Jones

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

11 Mar 2021

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Author response: Thank you for the reminder. We have reviewed the reference list and ensured that it is completed and correct.

Additional Editor Comments (if provided):

For this revision it was fortuitous to continue with the same peer reviewers from the initial submission. The sentiment from this review cycle is predominantly positive. Reviewer 2 notes an opportunity for slight adjustment to the manuscript discussion to enhance clarity and provide direction for future research efforts, as detailed below.

Response：Thanks you for your positive comments. We have revised the discussion section according to the Reviewer’s suggestion.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

________________________________________

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: (No Response)

________________________________________

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: Excellent revision. All of my major questions were addressed. One minor comment - authors discuss previous severity assessment tools (PSI/CURB-65), but these were intended for use to predict 30-day mortality in patients with community-onset pneumonia - it should probably be highlighted that these tools were never trained or designed for the use in patients with HAP. The lack of severity assessment tools specifically for this group of patients could rather be highlighted.

Response: Thanks for your comments. Based on your helpful suggestions, we have made the necessary corrections to our previous draft. Detail of the corrections in the discussion is provided below.

With regard to the severity of illness, previous studies have mainly focused on Pneumonia Severity Index (PSI) and CURB-65 score, which were mainly used to predict mortality in patients with CAP [30] and were seldom trained or designed in patients with HAP [31]. The lack of severity assessment tools specifically for this group of patients has limited the ability to early detection of poor prognosis among HAP patients. The current study added new evidence by exploring the role of chronic comorbidities in predicting HAP patients’ outcomes. We found that the ACCI score was an independent risk factor for mortality among HAP patients. The ACCI is widely used to predict mortality and has been validated in various clinical populations [21, 32]. The results support the prognostic value of the ACCI score and indicate that the ACCI score may be useful for risk stratification and decision making of individual HAP patients. Future studies are necessary to compare its performance with CURB-65 and PSI and determine if this tool may be universally applied to HAP patients.

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Barbara Jones

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: Response_letter_0311.docx

Click here for additional data file.

15 Mar 2021

Risk factors for 3 - month mortality in bedridden patients with hospital - acquired pneumonia: a multicenter prospective study.

PONE-D-20-25311R2

Dear Dr. Li,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Shane Patman, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

22 Mar 2021

PONE-D-20-25311R2

Risk factors for 3-month mortality in bedridden patients with hospital-acquired pneumonia: a multicentre prospective study.

Dear Dr. Li:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Assoc Prof Shane Patman

Academic Editor

PLOS ONE